This invention relates generally to the field of antineoplastic agents and more specifically to cyclophosphamide and formulations thereof suitable for use in parenteral administration.
Cyclophosphamide is one of the most significant antineoplastic drugs of today. Cyclophosphamide is disclosed and claimed in U.S. Pat. No. 3,018,302 granted Jan. 23, 1962 to H. Arnold et al., and is denoted chemically as 2-[bis(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine -2-oxide monohydrate.
Cyclophosphamide was initially commercially available as the monohydrate, in a parenteral dosage pre-mix consisting of a sterile, packaged, dry-powder admixture of the drug and sodium chloride. The premix was dissolved in water prior to administration which could be oral as well as parenteral.
The aqueous solution, however, necessitated prompt administration in that shelf-life was limited to several hours after preparation. Moreover, during processing and/or storage of the dry-powder pre-mix formulation, a glassiness and/or stickiness could be acquired by the pre-mix composition giving an unattractive material with inferior solubility characteristics and decreased potency. This deterioration was more pronounced as storage time was extended or if the upper limit of the storage temperature range was exceeded. This temperature sensitivity was problematic since common practice was to dissolve the solid cyclophosphamide pre-mix by heating the mixture, to expedite the dissolution process.
More recently, cyclophosphamide has become available as a lyophilizate. Although lyophilization is often employed for injectable pharmaceuticals which exhibit poor stability in aqueous solution, lyophilization was not applied to cyclophosphamide until around 1982.
As noted in Remington's "[t]he active constituent of many pharmaceutical preparations is present in such small quantities that if freeze-dried alone its presence would be hard to detect visually. Therefore, excipients are often added to increase the amount of solids present." Some such excipients which find common use are sodium or potassium phosphates, citric acid, tartaric acid, gelatin and carbohydrates such as dextrose, mannitol and dextran.
U.S. Pat. No. 4,537,883, issued to R. L. Alexander et al. pertains to a lyophilized cyclophosphamide. The '883 patent indicates that a storage-stable, lyophilized cyclophosphamide can be achieved provided that the lyophilizate retains some water of hydration and provided that mannitol is used as the sole excipient. More specifically, the lyophilized cyclophosphamide-mannitol solid composition of the '883 patent is alleged to have improved thermal stability when it contains an amount of water approximately equimolar to the cyclophosphamide content, taken as the anhydride. More importantly, the '883 patent states at column 3, lines 52-55, that the desirable, physical properties of the solid composition appear to be achieved only by using mannitol as the major excipient.
The '883 patent details an investigation of twelve different excipients, other than mannitol, which were used in attempts to produce a lyophilized cyclophosphamide, all unsuccessfully. Further, the '883 patent details the investigation of combinations of various excipients, none of which were useful in producing a usable lyophilized cyclophosphamide, except for certain combinations in which mannitol was the principal excipient.
Although the lyophilized formulations of cyclophosphamide, as shown in the '883 patent, have found commercial acceptance, a need continues to exist for alternate formulations of cyclophosphamide which do not require the presence of mannitol.